Despite the fact that many neurodegenerative diseases are age-related disorders, how aging predisposes the CNS to the development of neurodegenerative pathologies has not been adequately addressed. Numerous studies have documented an increase in inflammatory proteins in neurodegenerative diseases. However, whether age-related changes in inflammatory mediators are causally-linked to age-related disease progression is unknown. Our laboratory has shown that in Alzheimer's disease a pro-inflammatory cerebral vasculature releases neurotoxins and likely contributes to neuronal cell death. It is our hypothesis that age-related inflammatory changes in brain blood vessels contribute to age-related pathology in the brain. Because neuronal cell death is a central lesion in age-associated neurodegenerative diseases, we postulate a chain of events linking age-related increases in inflammation with vascular-mediated neuronal cell death. Aim 1- To determine if expression of inflammatory proteins increases in the cerebral vasculature with age. Fischer 344 rats at 6,12, 18, and 24 months of age are used to determine whether aging, in the absence of disease, affects vascular expression of inflammatory cytokines (IL-1beta, IL-6, IL-8, TNF-alpha) and chemokines (RANTES, MCP-1, MIP1-alpha). Inflammatory proteins are determined by ELISA, western and Northern blots, and real-time PCR and RT-PCR in isolated brain microvessels and by immunohistochemistry on tissue sections. Aim 2- To determine if age-related inflammatory changes are causally-linked to vascular mediated neuronal cell death. Our model predicts that in aging-vascular inflammation in the brain contributes to vascular-mediated neuronal cell death after injury. The cerebral microvasculature of Fischer 344 rats at 6,12,18, and 24 months is exposed to lipid or oxidative stress using both in vivo and in vitro injury models and vascular-mediated neuronal cell death assessed. Administration of anti-inflammatory drugs prior to injury is used to determine whether inhibiting inflammation prevents release of neurotoxic factors. These results would, for the first time, identify a mechanistic cascade linking age-related inflammatory changes to vascular mediated neuronal cell death. Results from this project could highlight a heretofore-unappreciated aspect of aging and suggest that approaches aimed at minimizing vascular inflammation and maintaining brain vascular function could be important for successful brain aging. [unreadable] [unreadable] [unreadable] [unreadable] [unreadable]